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PubMed1993

Characterization of the human cytochrome P450 isozymes responsible for styrene metabolism.

The rate of formation of styrene glycol from styrene was compared in human, rat and mouse liver microsomes. At a low styrene concentration (0.085 mM), the rates decreased in the order, mouse > rat > human; at a high concentration (1.85 mM), the order was rat > mouse > human. The forms of cytochrome P450 that are responsible for transforming styrene to styrene glycol were determined by vaccinia virus-mediated cDNA expression of individual P450 forms in cultured cells. Of the 10 human P450 forms studied, CYP2B6 was the most effective in forming of styrene glycol, followed by CYP1A2, CYP2E1 and CYP2C8; the human P450s CYP3A3, CYP3A4 and CYP3A5 also catalysed metabolism, but were much less active; and CYP2A6, CYP2C9 and CYP2D6 had little detectable activity. CYP1A1 from mouse liver was more active in forming styrene glycol than mouse CYP1A2; the latter was less active than human CYP1A2. CYP2B1 from rat liver was more active than rat CYP2B2 or CYP2B6 from human liver. The rate of styrene glycol formation was higher in lung microsomes from smokers than in those from current nonsmokers.

Animals↗
PubMed1993

The occupational scene of styrene.

Styrene readily undergoes homopolymerization as well as copolymerization with other monomers, such as acrylonitrile and butadiene. In closed polymerization processes, exposure of workers to styrene is generally lower than current reference values (20-50 ppm), but high peaks of exposure may occur during the cleaning, filling and maintenance of reaction vessels and during transport of liquid styrene. Styrene is used not only in styrene polymers but also as a reactive solvent in the manufacture of unsaturated polyester resins. During the lamination process, when resins are applied manually or by spraying in open moulds, workers are exposed to styrene at concentrations that are on average two or three times higher than the 8-h time-weighted average hygienic standard, 20 ppm. Further, exposures during the open mould process tend to fluctuate widely, so that short-term exposures are often twice the short-term reference value (100 ppm; 15-min time-weighted average). These processes also involve exposure to styrene oxide, which is a suspected carcinogen. Use of low-emission resins reduces exposure during curing but not during lamination itself. The exposure of laminators can be reduced by use of combined, carefully planned, general and local ventilation, adequately designed work places and promotion of safe working habits. The best way of controlling exposures to styrene in the reinforced plastic industry in general would be to automate the processes and to use closed moulds.

Air Pollutants, Occupational↗
PubMed1993

Effects of styrene on the reproductive health of women: a review.

Styrene has been shown to cross the placenta. Studies in animals suggest that styrene and styrene oxide have embryotoxic or fetotoxic effects early in pregnancy, but there is no evidence with regard to teratogenicity. This paper is a review of epidemiological investigations on the effects of occupational exposure to styrene on the reproductive health of women. The results of these studies are contradictory. Some early reports suggested that exposure to styrene induces menstrual disturbances, spontaneous abortions and congenital malformations. In more recent studies, no risk was observed among workers exposed to styrene in the reinforced-plastics industry. An excess of spontaneous abortions was, however, indicated by one investigation in women whose work included the processing of polystyrene. Two studies also suggested associations between exposure to styrene and low birth weight and reduced fertility. Although some epidemiological studies suggest that exposure to styrene involves reproductive hazards, the validity of most of these studies is weakened by methodological shortcomings. The available evidence cannot be used to draw any firm conclusions.

Abnormalities, Drug-Induced↗
PubMed1993

Dose-dependent kinetics of inhaled styrene in man.

One female and one male volunteer were exposed to styrene vapour (2 h; 50 W) at four different concentrations (26, 77, 201 and 386 ppm). Styrene levels were measured in arterialized capillary blood during and after exposure by head-space gas chromatography, and the levels of mandelic acid in urine were analysed by high-performance liquid chromatography. Non-linear relationships between the level of exposure to styrene and the concentration of styrene in arterial blood and 0-5 h cumulative excretion of mandelic acid indicated metabolic saturation. A physiologically based pharmacokinetic model was used to estimate the maximum metabolic rate (Vmax) of styrene from data on blood styrene. According to the model, the Vmax is 2.9 mmol/h, and metabolic saturation occurs at concentrations of 100-200 ppm styrene, depending on the level of physical activity. To our knowledge, this is the first time that dose-dependent kinetics of styrene has been shown in humans.

Administration, Inhalation↗
PubMed1996

Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.

We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf. Cigarette smoking was associated with significantly elevated GPA Vf among active smokers (P = 0.042 for phi/N and P = 0.020 for N/N) and among active and ex-smokers combined (P = 0.014 for N/N). Its influence on phi/N Vf was especially clear among active smokers in the control group (P = 0.005). An effect of smoking, nearly statistically significant, was also observed for the phi/N Vf of control ex-smokers (P = 0.055) and of all active and ex-smokers combined (P = 0.050). Thus, the two characterized chemical exposures experienced by this group of workers and controls appear to produce differential effects on the two independent classes of GPA variants enumerated in the assay. This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms. Styrene exposure is associated with a specific increase in GPA N/N Vf; these allele loss and duplication variants reflect predominantly somatic recombination mechanisms in erythroid progenitor cells. Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N Vf but also with an increase in phi/N Vf, reflecting the induction of GPA gene-inactivating mutations, including point mutations and deletions. This finding is consistent with a broad mechanistic spectrum of tobacco smoke genotoxicity associated with this complex mixture of chemical mutagens. Finally, there was no detectable effect of age on phi/N Vf; however, a highly significant (P = 0.0002) increase in N/N Vf with age, even after adjustment for other variables, was observed.

Adult↗
PubMedDate not supplied

Chronic toxicity/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks.

Groups of 70 male and 70 female Charles River CD-1 mice were exposed whole body to styrene vapor at 0, 20, 40, 80 or 160 ppm 6 h per day 5 days per week for 98 weeks (females) or 104 weeks (males). The mice were observed daily; body weights, food and water consumption were measured periodically, a battery of hematological and clinical pathology examinations were conducted at weeks 13, 26, 52, 78 and 98 (females)/104 (males). Ten mice of each gender per group were pre-selected for necropsy after 52 and 78 weeks of exposure and the survivors of the remaining 50 of each gender per group were necropsied after 98 or 104 weeks. An extensive set of organs from the control and high-exposure mice were examined histopathologically, whereas target organs, gross lesions and all masses were examined in all other groups. Styrene had no effect on survival in males. Two high-dose females died (acute liver toxicity) during the first 2 weeks; the remaining exposed females had a slightly higher survival than control mice. Levels of styrene and styrene oxide (SO) in the blood at the end of a 6 h exposure during week 74 were proportional to exposure concentration, except that at 20 ppm the SO level was below the limit of detection. There were no changes of toxicological significance in hematology, clinical chemistry, urinalysis or organ weights. Mice exposed to 80 or 160 ppm gained slightly less weight than the controls. Styrene-related non-neoplastic histopathological changes were found only in the nasal passages and lungs. In the nasal passages of males and females at all exposure concentrations, the changes included respiratory metaplasia of the olfactory epithelium with changes in the underlying Bowman's gland; the severity increased with styrene concentration and duration of exposure. Loss of olfactory nerve fibers was seen in mice exposed to 40, 80 or 160 ppm. In the lungs, there was decreased eosinophilia of Clara cells in the terminal bronchioles and bronchiolar epithelial hyperplasia extending into alveolar ducts. Increased tumor incidence occurred only in the lung. The incidence of bronchioloalveolar adenomas was significantly increased in males exposed to 40, 80 or 160 ppm and in females exposed to 20, 40 and 160 ppm. The increase was seen only after 24 months. In females exposed to 160 ppm, the incidence of bronchiolo-alveolar carcinomas after 24 months was significantly greater than in the controls. No difference in lung tumors between control and styrene-exposed mice was seen in the intensity or degree of immunostaining, the location of tumors relative to bronchioles or histological type (papillary, solid or mixed). It appears that styrene induces an increase in the number of lung tumors seen spontaneously in CD-1 mice.

Administration, Inhalation↗
PubMed2002

Liquid chromatography/electrospray tandem mass spectrometry characterization of styrene metabolism in man and in rat.

Liquid chromatography with electrospray tandem mass spectrometry was used to characterize the metabolism of styrene in man and in rat. To improve identification and characterization of minor styrene metabolites, rats were co-exposed to styrene and styrene-d(8). In addition to the main styrene metabolites, mandelic acid and phenylglyoxylic acid, and specific mercapturic acids, phenylhydroxyethylmercapturic acids (PHEMAs), other minor metabolites, including phenylglycine, N-acetyl-S-(phenacyl)cysteine, 4-vinylphenol and styreneglycol conjugates (glucuronides and sulfates) were identified and determined both in human and rat urine. Phenylglycine and N-acetyl-S-(phenacyl)cysteine have been hypothesized to occur, but never detected in human or rat urine after styrene exposure. 4-Vinylphenol and styrene glycol had already been recognized as styrene metabolites, but never determined as intact glucuronide and sulfate conjugates. Failure to identify 1- and 2-phenylethanol conjugates suggests that phenylethanol might be an intermediate metabolite, but it is not a conjugated catabolite. A method for the simultaneous determination of mandelic acid, phenylglyoxylic acid, phenyglycine and the four PHEMA diastereoisomers has been developed and validated. For those glucuronide and sulfate conjugates whose standards are not commercially available, a method for semiquantitative analysis, based on the use of structurally similar compounds as standards, has been developed. This approach was found to be valid for the determination of 4-vinylphenol glucuronide and 4-vinylphenol sulfate.

Acetylcysteine↗
PubMed1993

Styrene inhalation toxicity studies in mice. II. Sex differences in susceptibility of B6C3F1 mice.

Styrene is a commercially important chemical used in the production of plastics and resins. In initial short-term styrene inhalation studies, toxicity was significantly greater in male B6C3F1 mice than in females, suggesting that males may metabolize styrene more extensively and/or may be less able to detoxify reactive metabolites. In addition, a nonlinear dose-response was observed where toxicity and mortality were greater in mice exposed to 250 ppm than in those exposed to 500 ppm. These studies were conducted to investigate potential mechanism(s) for sex differences and the nonlinear dose-response in styrene toxicity by evaluating the effects of repeated styrene exposure on styrene oxide production, hepatic GSH availability, and hepatotoxicity in male and female B6C3F1 mice. Mice (36/sex/dose) were exposed to 0, 125, 250, or 500 ppm styrene 6 hr/day for up to 3 days. Styrene exposure caused increased mortality and hepatotoxicity (centrilobular necrosis, increased serum liver enzymes) in males and females after one or two exposures to 250 and 500 ppm. Hepatic GSH levels were decreased in a dose-dependent manner in males and females. After one exposure, GSH levels in males rebounded above controls in all dose groups. After three exposures to 125 or 250 ppm males appeared to maintain GSH levels; GSH was still decreased in the 500 ppm group. GSH levels in females were decreased after each exposure in all dose groups to lower levels than in males, and did not rebound above controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed2002

Physiologically based modeling of the inhalation kinetics of styrene in humans using a bayesian population approach.

Animal studies have implicated styrene as toxic to the central nervous system and its major metabolite styrene-7,8-oxide as a carcinogen. Therefore, a reliable estimate of the metabolic capacity for styrene in humans is of interest. However, the available models describing styrene kinetics in humans lack rigorous statistical validation and also ignore the population variability in metabolism. The population variability may be estimated by the use of population models. Furthermore, the statistical validation of pharmacokinetic models may be improved by use of Bayesian methods. These two approaches may be combined and recently have been gaining interest in the toxicology literature. A population-based physiologically based pharmacokinetic (PBPK) model for styrene was developed. The model was calibrated to extensive human toxicokinetic data from three previous studies in which 24 volunteers were exposed to 50-386 ppm of styrene at rest and various levels of exercise. Model fitting was performed in a Bayesian framework using Markov chain Monte Carlo simulation. The uncertainty around the partition coefficients and metabolic parameters for styrene was reduced. The metabolic capacity for styrene in humans was estimated to be 0.92 micromol/l kg(-1), with a lognormal standard deviation of 1.66. The estimated Vmax is 40% higher than previously estimated, whereas the population standard deviation is estimated for the first time.

Adolescent↗
PubMed1998

Metabolic interferences in subjects occupationally exposed to binary styrene-acetone mixtures.

OBJECTIVE: To investigate the excretion of styrene metabolites (mandelic acid, MA, and phenylglyoxylic acid, PGA) in workers employed in plastic manufacturing to verify the possible influence of coexposure to acetone on styrene metabolism. METHODS: This study was carried out on 50 workers employed in 3 factories producing polyester buttons. The workers were divided into three groups according to three different levels of acetone exposure. The trend of excretion for metabolites was examined during and after work shifts. Styrene and acetone were monitored on Thursday during the entire work shift by passive dosimeters placed on the lapel of the workers' uniforms, desorbed by carbon disulfide, and analyzed by gas chromatography. Biological monitoring was performed by determination of the urinary metabolites of styrene in urine samples collected on Thursday at the middle and the end of the work shift. MA and PGA were determined by a high-pressure liquid chromatographic method. RESULTS: The styrene concentrations ranged between 16 and 439 mg/m3, and in ten samples they exceeded the TLV-TWA (213 mg/m3). The acetone concentration ranged between 15 and 700 mg/m3 (TLV-TWA 1780 mg/m3), with the mean value being 208 mg/m3. During cleaning operations higher exposures to acetone demonstrated, with concentrations ranging between 500 and 3400 mg/m3. The amounts of MA and PGA determined at the end of workshifts did not significantly differ between the groups with different levels of acetone coexposure. Analysis of variance (ANOVA) between the groups confirmed that MA and PGA excretion did not significantly differ, although the metabolite values measured on the "morning of the day after" appeared higher in those groups with high levels of acetone exposure and were related to the average airborne concentrations of the solvent. In addition, the range and degree of correlation between styrene in air and biological levels of metabolites were modified by coexposure to acetone. CONCLUSIONS: Our data demonstrate that amounts of MA and PGA did not differ in groups with different levels of acetone exposure, but when the acetone air concentration increased the degree of correlation between styrene and MA and PGA decreased. Furthermore, coexposure to acetone levels similar to those described herein may hamper the use of urinary metabolites for the assessment of exposure to styrene, especially on an individual basis.

Acetone↗
PubMed2004

Response of human cord blood cells to styrene exposure: evaluation of its effects on apoptosis and gene expression by genomic technology.

Styrene is one of the most important monomers produced worldwide, and it finds major use in the production of polystyrene, acrylonitrile-butadiene-styrene resins and unsaturated polystyrene resins. Epidemiological studies on styrene showed that the malignancies observed most frequently in humans after exposure are related to the lymphatic and haemopoietic system. IARC classified styrene a possible carcinogenic to humans (Group 2B). In this study, we evaluated the effect of styrene on gene expression profiles of human cord blood cells, as well as its activity on the apoptosis and bcl-2 related protein expression. Data demonstrated that, after 24 and 48 h of exposure, styrene (800 microM) induced an increase in the necrosis of mononuclear cord blood cells, whereas it did not cause any increase in the apoptotic process. Western blot analysis revealed a modified expression of Bax, BCl-2, c-Jun, c-Fos and Raf-1 proteins in the human cord blood cells after direct exposure to styrene, whereas p53 expression did not change. Furthermore, Macroarray analysis showed that styrene changed cord blood gene expression, inducing up-regulation of monocyte chemotactic protein 1 (MCP-1), and down-regulation of CC chemokine receptor type 1 (CCR-1) and SLP-76 tyrosine-phosphoprotein.

Apoptosis↗
PubMed2001

DNA adducts, strand breaks and micronuclei in mice exposed to styrene by inhalation.

Genotoxic and clastogenic effects of styrene were studied in mice. Male NMRI mice were exposed by inhalation to styrene in concentrations of 750 and 1500 mg/m3 for 21, 7, 3 and 1 days (6 h/day, 7 days/week). Followed parameters included styrene in blood, specific styrene oxide (SO) induced DNA adducts, DNA strand breaks and micronuclei. The formation of SO induced 7-SO-guanines and 1-SO-adenines in DNA was analysed from lung tissues by two versions of the 32P-postlabeling technique. In lungs after 21 days of exposure to 1500 mg/m3 the level of 7-SO-guanine was 23.0+/-11.9 adducts/10(8) normal nucleotides, while 1-SO-adenine was detected at the levels of 0.6+/-0.2 adducts/10(8) normal nucleotides. Both 7-SO-guanines and 1-SO-adenines strongly correlated with exposure parameters, particularly with styrene concentration in blood (r=0.875, P=0.0002 and r=0.793, P=0.002, respectively). DNA breaks were measured in peripheral lymphocytes, bone marrow cells and liver cells using comet assay. To discern oxidative damage and abasic sites, endonuclease III was used. In bone marrow of exposed mice slight increase of strand breaks can be detected after 7 days of inhalation. A significant increase was revealed in the endonuclease III-sensitive sites after 21 days of inhalation in bone marrow. In the liver cells inhalation exposure to both concentrations of styrene did not virtually affect either levels of DNA single-strand breaks or endonuclease III-sensitive sites. The inhalation of 1500 mg/m3 of styrene induced significant increase of micronuclei after 7 days of exposure (10.4+/-2.5/1000 cells, i.e. twice higher micronuclei frequency than in controls). After 21 days of inhalation no significant difference between the control group and the two exposed groups was observed. Whether the decrease of micronuclei after 21 days of inhalation was due to the inhibition of cell proliferation caused by styrene or due to the natural elimination of chromatide fragments, remains to be clarified. An interesting link has been found between DNA single-strand breaks in bone marrow and frequencies of micronuclei (r=0.721, P=0.028).

Administration, Inhalation↗
PubMed2003

The ototoxic interaction of styrene and noise.

The interaction between noise and inhaled styrene on the structure and function of the auditory organ of the male Wistar rat was studied. The animals were exposed either to 600 ppm, 300 ppm or 100 ppm styrene (12 h/day, 5 days/week, for 4 weeks) alone or in combination with a simultaneous 100-105 dB industrial noise stimulant. Auditory sensitivity was tested by auditory brainstem audiometry at 1.0, 2.0, 4.0 and 8.0 kHz frequencies. Inner ear changes were studied by light microscopy. Exposure to 600 ppm styrene alone caused a 3 dB hearing loss only at the highest test frequency (8 kHz). Quantitative morphological analysis of cochlear hair cells (cytocochleograms) showed a severe outer hair cell (OHC) loss particularly in the third OHC row of the upper basal and lower middle coil. Exposure to noise alone caused only a mild hearing loss (2-9 dB), and only an occasional loss of OHCs (<1% missing). Exposure to the combination of noise and 600 ppm styrene caused a moderate flat hearing loss of 23-27 dB. The cytocochleograms showed a more severe damage of the OHCs than after exposure to 600 ppm styrene alone. The inner hair cells were found to be destroyed in some animals in the upper basal turn only after the combination exposure. Only in combination with noise exposure, the lower styrene concentrations (100 and 300 ppm) induced a hearing loss which was equivalent to that seen after exposure to noise alone. We conclude that: (1) There is an ototoxic interaction between styrene and noise. (2) Synergism is manifested only if styrene is applied in concentrations above the critical level (between 300 and 600 ppm in this study).

Animals↗
PubMed2004

Consequences of noise- or styrene-induced cochlear damages on glutamate decarboxylase levels in the rat inferior colliculus.

Both noise and styrene can injure the cochlea, resulting in a reduction of incoming inputs from the cochlea to the central nervous system. In addition, styrene is known to have neurotoxic properties at high doses. The loss of inputs caused by noise has been shown to be compensated by a new equilibrium between excitatory and inhibitory influences within the inferior colliculus (IC). The main goal of this study was to determine whether styrene-induced hearing loss could also be counterbalanced by a GABAergic adjustment in the IC. For this purpose, rats were exposed to noise (97 dB SPL octave band noise centered at 8 kHz), or to a non-neurotoxic dose of styrene for 4 weeks (700 ppm, 6 h/day, 5 days/week). Auditory sensitivity was tested by evoked potentials, and cochlear damage was assessed by hair cell counts. Glutamate decarboxylase (GAD) was dosed in the IC by indirect competitive enzyme-linked immunosorbent assay. Both noise and styrene caused PTSs that reached 27.0 and 14.6 dB respectively. Outer hair cell (OHC) loss caused by noise did not exceed 9% in the first row, on the other hand OHC loss induced by styrene reached 63% in the third row. Only the noise caused a decrease of GAD of 37% compared to that measured in the controls. No significant modification of GAD concentration has been shown after styrene exposure. Thus, central compensation for cochlear damage may depend on the nature of the ototoxic agent. Unless styrene directly affects IC function, it is reasonable to assume that noise causes a modification of inhibitory neurotransmission within the structure because of impairment of afferent supply to the auditory brainstem. The present findings suggest that central compensation for cochlear damage can preferably occur when afferent fibers are altered.

Animals↗
PubMed1975

The interaction of an epoxide with yeast alcohol dehydrogenase: evidence for binding and the modification of two active site cysteines by styrene oxide.

Yeast alcohol dehydrogenase is inactivated and alkylated by styrene oxide in a single exponential kinetic process. The concentration dependence of half-times for inactivation indicates the formation of an enzyme inhibitor complex, KI = 2.5 times 10(-2) M at pH 8.0. Reduced nicotinamide adenine dinucleotide (NADH), at a concentration of 3 times 10(-4) M where Kd congruent to 1 times 10(-5) M, has a small effect on kinetic parameters for inactivation. Although benzyl alcohol and acetamide-NADH increase the KI for styrene oxide in a manner consistent with their dissociation constants, substrate also increases the rate of inactivation at high styrene oxide concentrations. The reciprocal of half-times for inactivation, extrapolated to infinite styrene oxide concentration, increases with pH between 7.6 and 9.0, pK congruent to 8.5. The stoichiometry of alkylation by [3H]styrene oxide is 2.2 mol of reagent incorporated/mol of subunit, and is accompanied by the loss of 1.9 mol of sulfhydryl/mol of subunit; prior alkylation with iodoacetamide reduces the stoichiometry to 0.88:1, and increases the rate of labeling. Tryptic digests of enzyme modified with [14C]iodoacetamide or [3H]styrene oxide produce two major peptides which cochromatograph, indicating that styrene oxide and iodoacetamide modify the same cysteine residues. Previous investigators have reported that iodoacetate, iodoacetamide, and butyl isocyanate alkylate either of two reactive cysteines of yeast alcohol dehydrogenase; both cysteines cannot be modified simultaneously [Belke et al. (1974), Biochemistry 13, 3418]. The inactivation of enzyme by p-chloromercuribenzoate (PCMB) is reported here to be accompanied by the incorporation of 2.3 mol of PCMB/mol of enzyme subunits, in analogy with styrene oxide; the planarity of the alkylating agent appears to be an important factor in determining the stoichiometry of labeling.

Alcohol Oxidoreductases↗
PubMed2004

Reversal of enantioselectivity in the hydroformylation of styrene with [2S,4S-BDPP]Pt(SnCl3)Cl at high temperature arises from a change in the enantioselective-determining step.

Deuterioformylation of styrene catalyzed by [(2S,4S)-BDPP]Pt(SnCl(3))Cl at 39 degrees C gave 3-phenylpropanal (3) and 2-phenylpropanal (2) (n:i = 1.8, 71% ee (S)-2) with deuterium only beta to the aldehyde carbonyl and in the formyl group. Small amounts of deuterium were also found in the internal (2.8%), cis terminal (1.4%), and trans terminal (1.3%) vinyl positions of the recovered styrene. Deuterioformylation of styrene at 98 degrees C gave 3- (3) and 2-phenylpropanal (2) (n:i = 2.3, 10% ee (R)-2) with deuterium both alpha and beta to the aldehyde carbonyl and in the formyl group. Deuterium was also found in the internal (20%), cis terminal (12%), and trans terminal (12%) vinyl positions of the recovered styrene. These deuterioformylation results establish that platinum hydride addition to styrene is largely irreversible at 39 degrees C but reversible at 98 degrees C. Hydroformylation of (E)- and (Z)-beta-deuteriostyrene at 40 degrees C, followed by oxidation of the aldehydes to acids, and subsequent derivitization to the (S)-mandelate esters confirmed that 84% of 2-phenylpropanal (2) arises from platinum hydride addition to the si-face of styrene, while 73% of 3-phenylpropanal (3) arises from platinum hydride addition to the re-face of styrene. At 100 degrees C, the effect of variable H(2) and CO pressure on n:i, % ee, and TOF of hydroformylation of styrene was investigated. The results are consistent with enantioselectivity not being fully determined until the final hydrogenolysis of a platinum acyl intermediate.

Aldehydes↗
PubMed2004

Catalytic asymmetric heterogeneous aziridination of styrene derivatives using bis(oxazoline)-modified Cu2+-exchanged zeolite Y.

The copper-catalysed aziridination of styrene derivatives using either Cu(OTf)2 as a homogeneous catalyst or copper-exchanged zeolite Y modified as a heterogeneous catalyst with bis(oxazoline) using [N-(p-nitrophenylsulfonyl)imino]phenyliodinane (PhI=NNs) as nitrene donor is described and discussed. For the homogeneously catalysed reaction virtually all the substituted derivatives gave lower yields of the aziridine with lower ee when compared with styrene, although 4-chlorostyrene did give enhanced ee. For the heterogeneous catalysed reaction the styrene derivatives often gave enhanced yield, particularly when the substituent was in the 4-position. Particularly high ee was observed for 2-chlorostyrene (95%) and 4-chlorostyrene (94%) and in general the ee observed for the heterogeneously catalysed reaction with the 2- and 4-substituted derivates was significantly higher than that for the equivalent homogeneously catalysed reaction. With copper-exchanged zeolite Y the leaching of Cu2+ into solution during reaction was much lower for the substituted styrene derivatives (0.4-7% of total Cu) than with styrene itself (10.3% of the total Cu). The effect of reaction time on aziridine yield reveals an S-shaped profile that is accentuated by the position of the substituent and this effect is observed for both the homogeneously catalysed pathway and the heterogeneously catalysed reaction. A series of competitive experiments in which styrene was co-reacted with equivalent quantities of 2-, 3- and 4-chlorostyrene revealed that the reaction of styrene enhanced by the other substrate, but the rate of reaction of the substituted styrene was decreased. Co-reaction of 2- and 4-chlorostyrene reveals interesting competitive effects, which are discussed in terms of the nature of the active site.

Aziridines↗
PubMed1997

Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse.

1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N-acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting that metabolism was decreased; the SO/styrene ratio in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.

Adipose Tissue↗